Project Summary The overall goal of this proposal is to test a novel systemic Adenoviral therapy that targets transforming growth factor-? (TGF?) and reverses anti-PD-1 resistance to treat advanced breast and lung cancers. This STTR grant application illustrates the synergistic relationship between Dr. Prem Seth, inventor of a novel TGF-? decoy, and MultiVir Inc., a leader in clinical development of gene-based therapeutics. Dr. Seth has developed novel adenoviral vectors targeting TGF?, a well-recognized but largely undruggable oncology target. In addition, he has created a platform that can be delivered systemically, and specifically targets oncolytic adenoviral vectors to tumors. This oncolytic adenovirus vector has been engineered to reduce toxicity and the vector targets tumor cells via tumor-specific peptide. Dr. Seth has recently expanded his studies to examine if oncolytic adenoviruses targeting TGF? can overcome resistance to checkpoint inhibitor therapies (CKI; such as PD-1, CTLA-4). Although clinical studies have demonstrated encouraging response rates and long term survival in some breast cancer patients, it is clear that most patients do not respond or develop resistance to CKIs. Because of the critical role that TGF? plays in immunosuppression, angiogenesis and epithelial mesenchymal transition, a novel approach to overcoming CKI resistance would be to block TGF-? using a decoy receptor. We will use two well characterized tumor models, a mammary tumor and a lung cancer model in immunocompetent mice to conduct the following two Specific Aims. In Aim 1, we will examine if the intravenous administration of our vector results in reduced liver uptake, enhanced tumor uptake and targets TGF? pathways in the tumors and tumor-microenvironment. Aim 2 will determine if the intravenous delivery of vector can enhance efficacy of anti-PD-1-mediated therapy, and inhibit tumor growth and spontaneous metastases in an anti-PD1 resistant 4T1 mouse mammary and Lewis lung cancer mouse mammary tumor model. We believe that the pre-clinical research described here is critical to bring our therapeutic vector forward to its clinical evaluation. The proposed research aligns with MultiVir's research interests. MultiVir Inc. is highly supportive of this Phase1 STTR grant proposal, and if successful, plans to continue our collaborations with Dr. Seth, leading to the conduct of IND enabling studies as part of potential Phase 2 proposal.